From his Nobel autobiography: "By that time, I had elected to study biology and medicine, instead of going into the family business, as my father would have wanted. I did not realize, however, that admission to Medical School was a formidable undertaking for someone with my ethnic and foreign background in the United States of 1942. In spite of an excellent academic record at Columbia, I was refused admission by the numerous medical schools I applied to and would have found it impossible to study medicine except for the kindness and support of George W. Bakeman, father of a close friend, who was then Assistant to the President of the Medical College of Virginia in Richmond. Learning of my difficulties, Mr. Bakeman arranged for me to be interviewed and considered for one of the two remaining places in the Freshman class."[7]

At Columbia, Benacerraf got his start in Immunology with Elvin A. Kabat. He spent two years there working on experimental hypersensitivity mechanisms. He then moved to Paris because of family issues and accepted a position in Bernard Halpern's laboratory at the Hôpital Broussais. Here he also formed a close relationship with a young Italian scientist, Guido Biozzi. For six years he worked on the reticuloendothelial function in relation to immunity. The reticuloendothelia function is the white blood cells inside of a barrier tissue. While there they discovered techniques to study the clearance of particulate matter from the blood by the RES (reticuloendothelial system), and devised equations that govern this process in mammals. After six years Baruj returned to the United States because he could not make his own independent laboratory in France. In the U.S. he developed his own laboratory in New York City and returned to study on hypersensitivity. In New York, Baruj worked with several other immunologists on different fields of hypersensitivity. After working in his New York lab, Baruj turned his attention towards the training of new scientists. Also in this time frame Baruj made the decision to devote himself to his laboratory practices, instead of the family business. At this time Baruj also made the discovery that would go on to win him the Nobel Prize. He noticed that if antigens (something that causes a reaction with the immune system) were injected into animals with a similar heredity, two groups emerged: responders and non-responders. He then conducted further study and found that the dominant autosomal genes, termed the immune response genes, determined the response to certain antigens. This complex process would lead to the understanding of how these genes would determine immune responses.

His discovery still holds true, and more has been discovered over the last century. More than 30 genes have been discovered in a gene complex called the major histocompatibility complex. The histocompatibility complex is a complex part of DNA that controls the immune response. This research has also led to clarify auto immune diseases like multiple sclerosis and rheumatoid arthritis.[7]